Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11

Landrette, Sean F.; Kuo, Ya‐Huei; Hensen, Karen; Doorn-Khosrovani, Sahar van Waalwijk van Barjesteh; Perrat, Paola N.; Ven, Wim J.M. Van de; Delwel, Ruud; Castilla, Lucio H.

doi:10.1182/blood-2004-09-3630

Cited by 116 publications

(125 citation statements)

References 34 publications

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“…AML subtype M4 with eosinophilia is associated with a chromosome 16 inversion that creates a fusion gene CBFB-MYH11, encoding CBFbeta-SMMHC fusion protein. This fusion protein inhibits the core-binding factor (CBF), resulting in a block of hematopoietic differentiation and induction of leukemia in the presence of additional mutations (Landrette et al, 2005). It was also shown that PLAG1 and PLAGL2 expression was increased in 20% of human AML samples and, as was noted before, these transcription factors can increase proliferation of hematopoietic progenitors and increase cell renewal in vitro (Landrette et al, 2005).…”

Section: Chromosomal Deletion and Rearrangementmentioning

confidence: 69%

“…A recent microarray screening showed PLAGL1 to be among the genes whose expression were decreased in human intrauterine growth restriction (IUGR) placentae (McMinn et al, 2005). In contrast to LOT1 (PLAGL1/ZAC1), which was shown to be downregulated in cancer, PLAG1 and PLAGL2 expression was increased in human cancers including acute myeloid leukemia (AML) (Landrette et al, 2005).…”

Section: Gene Expression In Tumors and Cancer Cellsmentioning

confidence: 99%

“…The difference in function among the PLAG family members is thought to be due to difference in their DNA-binding capacity (Hensen et al, 2002). Plag1 and Plagl2 increased proliferation by inducing G1 to S transition that resulted in the expansion of hematopoietic progenitors and increased cell renewal in vitro (Landrette et al, 2005).…”

Section: Gene Expression In Tumors and Cancer Cellsmentioning

confidence: 99%

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LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Abdollahi

2006

Journal Cellular Physiology

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Lost-on-transformation 1 (LOT1) (PLAGL1/ZAC1) is a member of the novel subfamily of zinc-finger transcription factors, designated as PLAG family. The other members in this group include PLAG1 and PLAGL2, which share high homology with each other and with LOT1, particularly in their zinc-finger amino-terminal region. They are structurally similar but functionally different. For example, the LOT1 gene encodes a growth suppressor protein and is localized on human chromosome 6q24-25, a chromosomal region that is frequently deleted in many types of human cancers. The gene is maternally imprinted and is linked to developmental disorders such as growth retardation and transient neonatal diabetes mellitus (TNDM). LOT1 is a target of growth factor signaling pathway(s) and silenced by epigenetic mechanisms, as well as by the loss of heterozygosity in different tumor tissues. PLAG1 is a protooncogene that is localized on chromosome 8q12 and was found to be a target of several types of chromosomal rearrangement including the one identified in pleomorphic adenomas of the salivary gland. Since the discovery of the PLAG family members in 1997, much has been learned about their structure and function, as are summarized in this review. While the available data suggest that these proteins may play important roles in regulating normal physiological functions in the mammals, a great deal more about their signaling pathway(s), potential role in the complex pathologies such as cancer and developmental disorders, and functional relationship between different family members and splice variants still remains to be uncovered.

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Section: Chromosomal Deletion and Rearrangementmentioning

confidence: 69%

Section: Gene Expression In Tumors and Cancer Cellsmentioning

confidence: 99%

Section: Gene Expression In Tumors and Cancer Cellsmentioning

confidence: 99%

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LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Abdollahi

2006

Journal Cellular Physiology

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“…PLAG1 can promote the development of acute myeloid leukemia in cooperation with CBFb-SMMHC fusion protein in vivo. 8 These findings suggest that PLAG1 overexpression may have general importance in tumorigenesis.…”

mentioning

confidence: 75%

Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice

Zhao¹,

Ren²,

Yang³

et al. 2005

Intl Journal of Cancer

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Pleomorphic adenoma gene 1 (PLAG1) was found frequently rearranged and activated in human salivary gland pleomorphic adenomas. It encodes a developmentally regulated transcription factor. Ectopic overexpression of PLAG1 has been proposed to play a crucial role in tumorigenesis of salivary gland pleomorphic adenomas. It was reported that PLAG1 can activate the transcription of insulin-like growth factor 2 (IGF2), functioning as a protooncogene. In this report, we show that the salivary gland tumors developed in PLAG1 transgenic mice share major histopathologic features with human pleomorphic adenomas. It was found that b-catenin, the key component of Wnt signaling pathway, was upregulated at transcriptional level in tumors developed in 3 independent transgenic mouse lines. Immunohistochemical staining revealed that expression of b-catenin as well as c-myc, downstream of b-catenin in Wnt signaling pathway, was highly upregulated with overexpression of PLAG1 transgene in tumor and normal transgenic salivary gland tissues. Moreover, we found that PLAG1 can activate the transcription of mouse but not human b-catenin in the 3T3 cells cotransfected with reporter constructs. Sequence analysis shows there are 4 PLAG1 consensus binding sites in mouse b-catenin promoter region but not in human. Our findings provide the first in vivo evidence for the oncogenic activity of PLAG1 in pleomorphic adenoma tumorigenesis, reveal a valued animal model for human salivary gland tumors and suggest that Wnt signaling pathway may also contribute to the development of pleomorphic adenomas in transgenic mice. ' 2005 Wiley-Liss, Inc.Key words: pleomorphic adenoma gene 1; transgenic mice; b-catenin; pleomorphic adenomas The pleomorphic adenoma is the most common type of salivary gland tumor, which accounts for more than 50% of all salivary gland neoplasms. It usually behaves as the benign slow-growing tumor morphologically characterized by a biphasic pattern containing both epithelial and mesenchymal areas. 1 In recent years, a series of studies on tumorigenesis of salivary gland tumors has revealed that oncogenic activation of pleomorphic adenoma gene 1 (PLAG1) on 8q12 plays a crucial role in the development of pleomorphic adenomas originating from salivary glands. The major form of PLAG1 activation is reciprocal chromosomal translocations that lead to promoter swapping between PLAG1 gene, which is not expressed or weakly expressed in adult salivary glands, and the genes ubiquitously expressed in adult tissues, such as the b-catenin gene on 3p21, 2 the leukemia-inhibitory factor receptor (LIFR) gene on 5p13 and the transcription elongation factor SII gene on 3p21. 3-22. 3,4 The breakpoints of both fusion partner genes invariably occur in the 5 0 noncoding regions and consequently lead to ectopic expression of PLAG1 gene in salivary glands. In fact, the chromosomal translocations involving 8q12 only account for 39% of tumors. Other chromosomal abnormalities were also found to be associated with the formation of pleomorphic adenomas, such ...

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“…Mice expressing CBFb-SMMHC are phenotypically similar to AML1 (À/À) or CBFb (À/À) mice (Castilla et al, 1996;Okuda et al, 1996;Wang et al, 1996a, b). CBFb-SMMHC cooperates with ethylnitrosourea mutagenesis, mutation of the p16p19 cell cycle regulatory locus or coexpression of the PLAG1 or PLAGL2 transcription factors, to induce AML in mice (Castilla et al, 1999;Yang et al, 2002;Landrette et al, 2005;Moreno-Miralles et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Identification of a region on the outer surface of the CBFβ-SMMHC myeloid oncoprotein assembly competence domain critical for multimerization

et al. 2006

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In the core binding factor (CBF)b-smooth muscle myosin heavy chain (SMMHC) acute myeloid leukemia (AML) oncoprotein, CBFb lies N-terminal to the a-helical rod domain of SMMHC. Deletion of the SMMHC assembly competence domain (ACD), conserved among skeletal, smooth and nonmuscle myosins, prevents multimerization, inhibition of CBF and inhibition of cell proliferation. To define the amino acids critical for ACD function, three outer surface residues of ACD helices A-D, the subsequent helices E-H or the more N-terminal X or Z helices were now mutated. Variants were assessed for multimerization in low ionic strength in vitro and for nuclear localization as a measure of in vivo multimerization. Mutation of individual helices C-H reduced multimerization, with alteration of the outer surface of helices D or E having the greatest effect. The ability of these SMMHC variants to slow murine myeloid progenitor proliferation largely paralleled their effects on multimerization. Divergence at the boundaries of the ACD may reflect quantitative differences between in vitro and in vivo filament assembly. Each helix mutant retained the ability to bind the mSin3A corepressor. Agents interacting with the outer surface of the CBFb-SMMHC ACD that prevent multimerization may be effective as novel therapeutics in AML.

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Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11

Cited by 116 publications

References 34 publications

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice

Identification of a region on the outer surface of the CBFβ-SMMHC myeloid oncoprotein assembly competence domain critical for multimerization

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